Submissions for variant NM_014249.4(NR2E3):c.227G>A (p.Arg76Gln)

gnomAD frequency: 0.00029  dbSNP: rs104894493

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000261496	SCV000393760	uncertain significance	NR2E3-Related Disorders	2016-06-14	criteria provided, single submitter	clinical testing	The c.227G>A (p.Arg76Gln) variant has been reported in one patient with enhanced S-cone syndrome and in a second patient with retinitis pigmentosa. The zygosity state of the variant is unknown in both patients (Haider et al. 2000; van Huet et al. 2015). The p.Arg76Gln variant was absent from 500 controls and is reported at a frequency of 0.00064 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Functional studies demonstrated the p.Arg76Gln variant leads to subcellular mislocalization, absent DNA binding activity, and reduction of NR2E3-mediated increase in transcriptional activity (Kanda et al. 2009; Roduit et al. 2009). The evidence for this variant is limited. The p.Arg76Gln variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for NR2E3-related disorders.
Counsyl	RCV000668029	SCV000792572	uncertain significance	Enhanced S-cone syndrome; Retinitis pigmentosa 37	2017-07-10	criteria provided, single submitter	clinical testing
Invitae	RCV001045323	SCV001209164	pathogenic	not provided	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 76 of the NR2E3 protein (p.Arg76Gln). This variant is present in population databases (rs104894493, gnomAD 0.04%). This missense change has been observed in individuals with autosomal recessive retinal dystrophy (PMID: 30324420; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5530). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NR2E3 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects NR2E3 function (PMID: 19823680, 19898638, 27013732). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001075864	SCV001241503	pathogenic	Retinal dystrophy	2019-08-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001045323	SCV001247329	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	NR2E3: PM3:Very Strong, PM2, PM5, PP1:Moderate, PS3:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000005867	SCV001366569	pathogenic	Enhanced S-cone syndrome	2019-03-12	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PM5.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001045323	SCV001447893	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001449793	SCV001653074	likely pathogenic	Goldmann-Favre syndrome	2020-07-03	criteria provided, single submitter	clinical testing	The p.Arg76Gln variant in NR2E3 has been reported in at least 3 homozygous and 2 compound heterozygous individuals with retinal disorders (Haider 2000 PMID: 10655056, Schorderet 2009 PMID: 10655056, Li 2017 PMID: 28418496, Stone 2017 PMID: 28559085, Murro 2019 PMID: 30324420). It has also been identified in 0.038% (45/119410) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive allele frequency. This variant has also been reported in ClinVar (Variation ID: 5530). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies provide evidence that this variant impacts protein function (Kanda 2009 PMID: 19898638, Roduit 2009 PMID: 19823680); however, these types of assays may not accurately represent biological function. Another variant involving this codon (p.Arg76Trp) has been identified in individuals with retinal disease, suggesting change at this residue may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Enhanced S-Cone syndrome. ACMG/AMP Criteria applied: PM3_Strong, PS3_Moderate.
GeneDx	RCV001045323	SCV001813632	pathogenic	not provided	2022-11-29	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19823680, 19898638, 27013732, 28418496, 10655056, 30324420, 19718767, 34426522, 31980526, 32679203, 32531858, 28559085, 26667666)
Revvity Omics, Revvity	RCV001045323	SCV002018368	pathogenic	not provided	2022-09-12	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000005867	SCV002556562	likely pathogenic	Enhanced S-cone syndrome	2021-02-03	criteria provided, single submitter	clinical testing	PS3
Baylor Genetics	RCV000005867	SCV004191582	pathogenic	Enhanced S-cone syndrome	2023-10-30	criteria provided, single submitter	clinical testing
OMIM	RCV000005867	SCV000026049	pathogenic	Enhanced S-cone syndrome	2000-02-01	no assertion criteria provided	literature only
Clinical Genetics, Academic Medical Center	RCV001045323	SCV001925426	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001045323	SCV001951208	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001045323	SCV001964451	pathogenic	not provided		no assertion criteria provided	clinical testing